Ox40 mediated co-stimulation overcoming tumor-induced CD8 T cell peripheral toler

项目总结/摘要 肿瘤特异性CD 8 T细胞外周耐受性可能是产生有效抗肿瘤免疫应答的主要障碍。 肿瘤免疫最近的研究已经开始检查是否通过共刺激信号 分子可以充分增强免疫应答以逆转肿瘤特异性耐受， 提高抗肿瘤免疫力。为此，我们的实验室和其他人专注于 OX 40（CD 134）共刺激分子的连接机制， 肿瘤坏死因子受体（TNFR）超家族，增强CD 4和CD 8 T细胞扩增， 分化和生存。重要的是，几项研究还表明，OX 40表达于 从携带肿瘤的宿主的肿瘤引流淋巴结中分离的T细胞， 参与可以增强体内抗肿瘤免疫力。OX 40介导的信号传导也被证明是 克服肽诱导的CD 4 T细胞无能。最近，我们证明了OX 40连接可以 在体内恢复无反应性肿瘤反应性CD 8 T细胞的功能。虽然抗OX 40治疗导致 肿瘤部分消退，肿瘤最终复发。因此，了解这些机制 调节肿瘤特异性无反应性的诱导可能会导致新的治疗方法的开发， 增强CD 8 T细胞介导的抗肿瘤免疫的策略。在本提案的目标I中，我们将 研究共同γ链（gc）细胞因子IL-2和IL-4调节的机制 CD 8 T细胞上的OX 40受体表达，包括调节活化的分子机制 OX 40启动子在目标II中，我们将确定肿瘤诱导的分子机制。 CD 8 T细胞无反应性，并测试联合抗OX 40/gc细胞因子治疗可以恢复的假设 无反应性CTL在荷瘤宿主中的功能。目的III旨在检验抗OX 40抗体 治疗可以增强患有肿瘤的小鼠中内源性肿瘤特异性CD 8 T细胞的分化。 自发发生的前列腺癌，并测试抗OX 40治疗是否促进前列腺癌的发生。 目前正在接受化疗的癌症患者中肿瘤反应性CD 8 T细胞的分化 激动剂抗OX 40 mAb在EACRI的I期临床试验中。这些研究将 提供了深入了解调节OX 40表达的机制，肿瘤的分子基础， 特异性CD 8 T细胞无反应性，以及抗OX 40治疗是否可以增加内源性CD 8 T细胞 在荷瘤小鼠和癌症患者中的反应。

Project Summary/Abstract Tumor-specific CD8 T cell peripheral tolerance can be a major barrier to the generation of potent anti- tumor immunity. Recent studies have begun to examine whether signaling through co-stimulatory molecules can sufficiently boost the immune response to reverse tumor-specific tolerance and promote anti-tumor immunity. To this end, our laboratory and others have focused on the mechanisms through which ligation of the OX40 (CD134) co-stimulatory molecule, a member of tumor necrosis factor receptor (TNFR) super-family, augments CD4 and CD8 T cell expansion, differentiation, and survival. Importantly, several studies have also shown that OX40 is expressed on T cells isolated from the tumor-draining lymph nodes of tumor-bearing hosts and that OX40 engagement can boost anti-tumor immunity in vivo. OX40-mediated signaling has also been shown to overcome peptide-induced CD4 T cell anergy. Recently, we demonstrated that OX40 ligation could restore the function of anergic tumor-reactive CD8 T cells in vivo. Although anti-OX40 therapy led to partial tumor regression, the tumors ultimately recurred. Thus, understanding the mechanisms regulating the induction of tumor-specific anergy may lead to the development of new therapeutic strategies to enhance CD8 T cell-mediated anti-tumor immunity. In Aim I of this proposal, we will investigate the mechanisms by which the common gamma chain (gc) cytokines IL-2 and IL-4 regulate OX40 receptor expression on CD8 T cells including the molecular mechanisms regulating activation of the OX40 promoter. In Aim II, we will determine the molecular mechanisms by which tumors induce CD8 T cell anergy and test the hypothesis that combined anti-OX40/gc cytokine therapy can restore the function of anergic CTL in tumor-bearing hosts. Aim III seeks to test the hypothesis that anti-OX40 therapy can enhance the differentiation of endogenous tumor-specific CD8 T cells in mice with spontaneously arising prostate cancer and to test whether anti-OX40 therapy promotes the differentiation of tumor-reactive CD8 T cells in cancer patients that are currently being treated with an agonist anti-OX40 mAb in a phase I clinical trial at the EACRI. Taken together, these studies will provide insight into the mechanisms regulating OX40 expression, the molecular basis of tumor- specific CD8 T cell anergy, and whether anti-OX40 therapy can augment the endogenous CD8 T cell response in both tumor-bearing mice and cancer patients.